Process for coating pharmaceutical preparations with a hydroxy propyl methyl cellulose-sealing agent moisture-preventing film



United States Patent PROCESS FOR COATING PHARMACEUTICAL PREPARATIONSWITH A HYDROXY PROPYL METHYL CELLULOSE-SEALING AGENT MOIS-TURE-PREVENTING FILM Yoji Tuji, Osaka, Japan, assignor to SumitomoChemical 0., Ltd., Osaka, Japan No Drawing. Filed Apr. 25, 1966, Ser.No. 544,687

Claims priority, application Japan, May 7, 1965, 40/ 27,191 Int. Cl.C09d 3/08, 3/18, 3/80 US. Cl. 106-151 2 Claims ABSTRACT OF THEDISCLOSURE A composition useful for applying a moisture-preventingcoating on tablets comprising hydroxypropylmethylcellulose, of which theviscosity in 2 weight percent aqueous solution is below 10 cps. at 20C., dissolved in a mixture of at least one low boiling aliphatic halideand at least one other solvent, which may be an alcohol, mixtures ofalcohol and a ketone or mixtures of water and an alcohol, and a sealingagent which may be a copolymer of butyl methacrylate anddimethylaminoethly methacrylate, shellac or a prolamin. The presentdisclosure also provides for a process of coating tablets with the abovecomposition.

The present invention relates to a process for coating pharmaceuticalpreparations such as tablets, pills and granules with amoisture-preventing and thermostable film to enhance the moisturebarrier, facilitate the administration, preserve the beautifulappearance and make it possible to package them easily withhot-processing materials. ,1

In recent years, tablets, pills, granules and the like are much oftenrequired to be coated depending on their chemical and physicalproperties and their use. Although a number of compositions for coatingare known, they can not always furnish satisfactory moisture barrier,disintegration property and thermostability to such peparations.

Namely, when preparations are coated with a composition containingpolyethylene glycol 2,000 to 6,000 as the principal ingredient, thesticking due to the hygrosropicity occurs at the critical relativehumidity of about 70%. As the films adhere together even under a tepidcondition, the strip packaging with a heat sealer encounters difficulty.

When polyoxyethylene polymers (molecular weight more than 20,000) areemployed, the viscosity of the coating solution is high. Due to itsthreading property, the coating operation is effected with diflicultyand, in most cases, the coating by spraying hardly accomplished.

Moreover, most of synthetic and natural resins used for coating areeasily soluble in organic solvents but sparingly soluble in water. Sincethe most widely used cellulose acetate phthalate does not dissolve inwater and gastric juice and dissolves in intestinal juice, it cannot beproperly used for coating such medicines as desiredto exert rapidly theremedial effect.

The present inventors have studied on the process for coating tabletswith a film having no disadvantages as mentioned above. As the result,there has been discovered an excellent film which is moisture-proof,unchanged on heating about 65 C., rapidly disintegrated in wateror,artificial gastric junce and of smooth and glossy surface, the saidfilm being formed by dissolving in a mixture of a low-boiling aliphatichalide solvent such as dichloromethane and a low-boiling organic solventsuch as methanol or ethanol, hydroxypropylmethylcellulose of which3,477,864 Patented Nov. 11, 1969 ice the viscosity in 2% aqueoussolution is below 10 cps. at 20 0, adding thereto adimethylaminoacrylate resin, shellac or a prolamin, -i.e. zein, with orwithout a coloring agent, a plasticizer, a polishing material, aseasoning and the like, spraying the resultant coating solution ontablets rolling in a coating pan according to the impacted or compressedair process, drying and effecting repeatedly the latter two operations.

The hydroxypropylmethylcellulose used in the present invention is acellulose derivative which contains about 7 to 12 weight percent ofhydroxypropyl groups and about 28 to 30 weight percent of methoxy groupsand the viscosity in 2% aqueous solution is below 10 cps. at 20 C. Thus,even when used at a high concentration, it does not hinder the coatingoperation so that the. time for processing is shortened, the solventsaved, the procedure for coating much simplified and a uniform andsmooth film formed easily.

The dimethylaminoacrylate resin employed in the present invention is acopolymer of butyl :methacrylate and dimethylaminoethyl methacrylate. Itdissolves below pH 2 and considerably swells at pH 3 to 6 to let waterpermeate through the same.

When employed alone, the former of the said two polymers shows poormoisture-proof property and, on coating by spraying, forms a less glossysurface. The latter has a peculiar color tone and causes difiiculty inthe coating operation. The combined use of these two polymers, however,can provide the most ideal film. The use of shellac or a prolamin, i.e.zein, in place of the dimethylaminoacrylate resin may also furnish animproved moisture-proof property and an excellent glossy surface totablets without afiecting their disintegration time in artificialgastric juice.

Furthermore, the film prepared by the present process may serve as aso-called protective coating for preventing tablets from penetration ofwater in the course of sugar or gelatin-coating.

The plasticizers which may be used in the present invention are esterssuch as dimethyl phthalate, dibutyl phthalate, triacetin and isopropylmyristate, surfactants of low HLB (Hydrophil Lipophile Balance) such aspolyoxyethylene aliphatic acid esters, castor oil and the like. As thecoloring agent, there may be employed a lake or a dye which is solublein organic solvents. As the polishing material, there may be used one ormore of natural and synthetic wax and waxlike substances such ascarnauba wax, hardened castor oil and beeswax. It is the most effectiveto use them together with talc, magnesium stearate, calcium stearate,aluminum stearate or the like in suspension.

Table 1 illustrates that the combined use ofhydroxypropylmethylcellulose with the dimethylaminoacrylate resin,shellac or zein enhances the moisture barrier of the formed film,compared with the single use of the said cellulose.

In Tables 2 to 4, the moisture barrier, the thermostability and thefacility of disintegration of the coated tablets prepared by the presentprocess are compared with those of the coated tablets prepared by theheretofore most widely adopted coating process employing polyethyleneglycol 6,000 and cellulose acetate phthalate as the principalingredients.

EXAMPLE 1 Twenty grams of 12.5 weight percent solution ofdimethylaminoacrylate resin in a mixture of acetone and isopropanol and20 g. of hydroxypropylmethylcellulose are dissolved in a mixture of 220g. of ethanol and g. of trichloroethylene. To the resultant mixture,there are added 1 g. of castor oil, 6 g. of diethyl phethalate and a hotsolution of 2 g. of carnauba wax and 1 g. of hardened castor oil in 60g. of trichloroethylene. In the resulting EXAMPLE 3 mixture, there aresuspended 2 g. of magnesium stearate,

3 g. of titanium dioxide and 15 g. of talc by the aid of a Twenty gramsof hydroxypropylmethylcellulose and homogenizer or the like. Anappropriate amount of the g. of medicinal shellac are dissolved in amixture of 80 thus Obtained coating Solution is p y With an p y 5 g. ofethanol and 80 g. of trichloroethylene. Separately, 81111 of 1 t0 0113,000 COHVeX-SUTfaCe tablets 6011- there is prepared a homogeneoussuspension of 2 g. magsisting of 22 parts of sodium chloride, 22 partsof sl nesium stearate, 2 g. of titanium dioxide, 15 g. of talc, 33 Partsof lactose, 22 Part8 of corn Starch and 1 0.1 g. of saccharin sodium,0.9 g. of sodium cyclamate p of magnesium stearate and rolling in asugar coating and 1 to 2 g. of a color lake in 40 g. of ethanol. To apan, each tablet being 9 mm. in diameter and 280 mg. mixture of thesolution and the suspension prepared above, in Weight Instantly afterthe p y is Completed, hot there is added a hot solution of 6 g. ofdiethyl phthalate,

air is blown into the pan to dry the tablets. This proce- 1 g, of castoroil, 1.5 g. of carnauba wax and 1 g. of dure is repeated to form a filmweighing to mghardened castor oil in 60 g. of trichloroethylene. Thetabper tablet. lets used in Example 1 are coated with the resultantcoat- T C ated ta s thus P p have a White, glossy 15 iug solution in thesimilar manner to produce the coated and graceful appearance. Theirmoisture barrier, thermotablets having a glossy and graceful appearance.Their stability and facility of disintegration re a isfactory asmoisture barrier, thermostability and facility of disinteshown in Tables2, 3 and 4. gration are satisfactory as shown in Tables 1, 2, 3 and 4.

EXAM1 ).LE 2 2O EXAMPLE 4 Twenty grams of 12.5 weight percent solutionof di- .methylaminoacrylate resin in a mixture of isopropanol TWent ramsof h drox r0 lmeth lceuulose and 5 and apetone 2 20 ofhydroxypropylmethylcfiuulose g. of zeiii Ere dissolvei in a i nix tiireof 80 g. of ethanol, are dissolved 1n 80 g. of ethanol and 80 g. oftrichloro- 80 g of trichloroethylene and 5 of water Separately ethyleneseparately there is .prepared a homogeneous there is prepared ahomogeneous suspension of 2 g. 0% Suspension of 2 of magneslum Smarate 3of magnesium stearate, 2 g. of titanium dioxide, 15 g. of

nium dioxide, 15 g. of talc, 0.1 g. of saccharin sodium, 0.9 g. ofsodium cyclamate and 1 to 2 g. of a color lake in 40 g. of ethanol. Thesuspension thus obtained is mixed with the above prepared solution. Tothe resulting mixture, there is added a hot solution of 3 g. ofisopropyl talc, 0.1 g. of saccharin sodium, 0.9 g. of sodium cyclamateand l to 2 g. of a color lake in g. of ethanol. To a'mixture of thesolution and the suspension prepared above, there is added a hotsolution of 6 g. of diethyl myristate, 3 g. of polyoxyethylene stearate,1 g. of castor Phthalate! 1 Castor Q of carflauba Wax and Oil 15 ofcarnauba wax and 1 of hardened Castor 1 g. of hardened castor O1]. in 60g. of trlchloroethylene. oil in 60 g. of trichloroethylene. The tabletsemployed in The tabletshsed t p a coated With the Example 1 are coatedwith the resultant coating solution 35 Sultant Coatlng Solutloh 1n the511111131 manner to Produce in the similar manner to produce the coatedtablets havthe Coated tablets having a glossy and graceful pp ring aglossy and graceful appearance. Their moisture barance. Their moisturebarrier, thermostability and facility rier, thermostability and facilityof disintegration are satof disintegration are satisfactory as shown inTables 1, isfactory as shown in Tables 1, 2, 3 and 4. 2, 3 and 4.

TABLE l.-HYGROSCOPICITY TEST AT RELATIVE HUMIDITIES OF 75%, 82% and 91%at 37 C.

Tablets coated with coating solution comprisinghydroxypropyhnethylcellulose as Coated tablets obtained Coated tabletsobtained Coated tablets obtained Uncoatcd tablets principal ingredientin Example 2 in Example 3 in Example 4 RH RH RH RH RH RH RH RH RH RH RHRH RH RH 82% 91% 75% 82% 91% 75% 82% 91% 75% 82% 91% 75% 82% 91% 1.21 1. 28 0. 34 0. O. 56 0. 18 0. l9 0. 22 0. 14 O. 16 0. 21 0. 16 0. 190. 23 1. 39 1.62 0. 62 0.73 0. 83 0.31 0 35 0. 41 0. 22 0.27 0.33 0.260.31 0.39 6.05 8. 91 3. 25 4. 35 5. 17 1. 63 1 68 2. 65 1. 38 1. 56 2.61 1. 62 1. 7O 2. 93 9. 53 28.0 6.20 7. 42 19. 3. 24 3 51 6. 54 2.033.10 9.15 2. 57 3. 25 10. 03 15. 13. 20 33. 6 8. 40 9. 56 23. 8 4. 31 4.73 10. 15 3. 25 4.02 10. 20 3. 75 4. 35 12. 50 96 hours.-. 20.00 17.344.0 12.70 14. 32 32. 5 6.35 7 23 15.28 5. 51 6 35 15. 59 5. 65 6.8317.05

TABLE 2.-THERMO STABILITY TEST Coated tablets obtained b the res tTablets coated with coating solution comprising cellulose acetate y p enp1 ocess phthalate and polyethylene glycol 6,000 as principalingredients Example 1 49 C. C. C. 49 C. 55 C. 65 C.

Unchanged Unehanged Sticked. Unchan od. Unchan ed U l do Sticked Surfacepartly dissolveddo). "don lh g o Do. do. o do.. Do.

Coated tablets obtained by the present process Example 2 Example 3Example 4 Time 49 C. 55 C. 65 C. 49 C. 55 C. 65 C. 49 C. 55 C. (35 C.

2 hours Unchanged- Unchanged. Unchanged- Unchanged- Unchan ed- Unchaned- Uncha d U ha 6 hours do do .110 ..d0 d0. do.. new??? .li aoffii'.iiii .do Do TABLE 3 Tablets coated with coating solution comprisingcellulose acetate phthalate and polyethylene glycol 6,000 as principalingredients Coated tablets obtained in Example 1 Time RH 75% RH 82% RH96% RH 75% RH 82% RH 96% Sticked Sticked Unchanged Unehanged Unchanged.

Surfgce dissolved Surface dissolved. (1 Do.

o. Do. Partly disintegrate Do. do do Less glossy. Partlydisintegrated..- Almost disintegrated Less glossy Swelled. 96 hours ..do.do .do do. Not glossy Cracked.

Coated tablets obtained in Example 2 Coated tablets obtained in Example3 Coated tablets obtained in Example 4 RH 75% RH 82% RH 96% RH 75% RH82% RH 96% RH 75% RH 82% RH 96% Uncranged- Un changerL Unchanged.Unchanged Unchanged- Unchanged- Unchanged- Unchanged Unchanged. do0..... "do" do do .do ,.d Do.

0..." do. Not glossy Swelled- Less glossy do 96 hours do Swelled Crackeddo -do Swclled NOTE.-RH= Relative Humidity.

TABLE 4 Tablets coated with coating solution comprising celluloseacetate phthalate and polyethylene Coated tablets obtained by thepresent process Uncoated glycol 6,000 as printablets cipal ingredientsExample 1 Example2 Example3 Example l Water 5'6 30-40 8l0 810 '-151o'-12. Artificial gastric juice 56 40450 8-10' s'10' 10'-15' 10'-12'What is claimed is: of butyl methacrylate and dimethyl arninoethylmeth- 1. A process for applying a moisture-preventing coatacrylate,shellac or a prolarnin. ing on solid pharmaceutical preparation in theform of tablets, pills and granules, which comprises (1) pre- FReferences Cited paring a coating composition by dissolving hydroxy-UNITED STATES PATENTS propylmethylcellulose, of which the viscosity in 2weight percent aqueous solution is below 10- cps. at 20 C., in g; g l 12 a mixture of at least one low boiling aliphatic halide and 28874405/1959 at least one low boiling organic solvent selected from 29418936/1960 Mreglmger g the group consisting of alcohols, mixtures ofalcohols 2948626 8/1960 S c donnaug ay K 5 and ketones and mixtures ofalcohol and water, and 3132075 5/1964 g ers adding to the resultingsolution a sealing agent selected 3116205 12/1963 5 26 1 from the groupconsisting of a copolymer of butyl meth- 3244596 4/1966 L at a 25 5acrylate and dimethylaminoethyl methacrylate, shellac 0 11 9 6 or aprolarnin, (2) spraying the coating composition onto 8 9 /1 6 ohnson 42435 the solid pharmaceutical preparations being rolled in a OTHERREFERENCES usual Coating (3) drying the coated Preparations ChemAbstract: :36-78d f Westerburg Tablet coatand (4) repeating the sprayingand drying. and Neth, &Pp1 6502190 2. A composition comprisinghydroxypropylmethyl- 0 cellulose, of which the viscosity in 2 weightpercent HAROLD D ANDERSON, Primary Examiner aqueous solution is below 10cps. at 20 C., dissolved in a mixture of at least one low boilingaliphatic halide WOODBERRY, Asslstam Examlner and at least one lowboiling organic solvent selected from the group consisting of alcohols,mixtures of alcohols and K5 ketones and mixtures of alcohol and water,and a sealing 106-173; 260-17; 424--35 agent selected from the groupconsisting of a copolymer

